By Christos Krogias, on behalf of ENS, Ruhr University Bochum, Germany
Michel Clanet, on behalf of ECTRIMS and ENS, University of Toulouse, France
Giancarlo Comi, on behalf of ENS, University Vita-Salute San Raffaele, Milan, Italy
Ralf Gold, on behalf of ECTRIMS and EFNS, Ruhr University Bochum, Germany
Gian Luigi Lenzi, on behalf of EFNS, University of Rome, Italy
Xavier Montalban, on behalf of ECTRIMS, University of Barcelona, Spain
Per Soelberg Sørensen, on behalf of ECTRIMS and EFNS, University of Copenhagen, Denmark
Multiple sclerosis (MS) is a chronic, primarily inflammatory demyelinating disease of the
central nervous system (Compston and Coles, 2008). Pathogenesis is triggered by
environmental factors in combination with genetic susceptibility. Typically migration of
autoreactive lymphocytes across the blood-brain barrier initiates the activation of a complex
autoimmune cascade, where monocytes and microglial cells then step in and further
augment tissue damage by oxidative mechanisms. The histological hallmark of the disease is
a perivenous sclerotic plaque, characterised by inflammation, oligodendrocyte depletion,
astrocytosis, de- and remyelination as well as subsequent axonal degeneration (Lucchinetti
et al., 2000).
This perivenous formation of the plaque has set the stage to introduce the hypothesis that a
venous blockade may stand at the beginning of the chronic autoimmune process and may
thus represent the true pathogenetic cause of the disease. A putative venous congestion has
been discussed as a contributing factor to the pathogenesis of MS already 30 years before
(Allen, 1981).
This discussion was resurrected in the year 2006 by Paolo Zamboni from Ferrara, Italy, who
proposed parallels between an iron-dependent inflammation in chronic venous insufficiency
(CVI) of the lower limbs and the perivenously located white-matter lesion in MS. He stated
that his considerations may represent ?The big idea? (Zamboni, 2006). Three years later,
Zamboni et al. reported an impressive coincidence of MS and venous stenoses
demonstrated with ultrasound investigations in various locations of deep cervical veins
(Zamboni et al., 2009). This concept was then named "chronic cerebrospinal venous
insufficiency (CCSVI). In this concept it is hypothesized that a blockage of venous flow leads
to an increased venous blood pressure in the central nervous system, which in turn causes
congestional bleeding with perivenous iron accumulation and subsequent inflammatory
reactions (Zamboni 2009a).
In considering CCSVI as a highly specific finding in MS, it should be remembered that
cerebral venous insufficiencies were already discussed as a causal factor in other
neurological diseases such as transient global amnesia or idiopathic intracranial
hypertension (Schreiber et al., 2005; Nedelmann et al., 2009). Furthermore, other conditions
such as neck-dissection surgery result in changed venous outflow (Gius and Grier, 1950).
There is no scientifically proven evidence for a higher incidence of MS in such patients with
confirmed venous obstruction, so that serious doubts are raised about the conceptual
plausibility of CCSVI as a significant factor. In addition, the spectacular findings of Zamboni
et al., reporting not only a high specificity but also a high sensitivity of venous pathology in
MS, could not be reproduced by other groups.
In a small cohort of unselected MS-patients and matched controls in Bochum, Germany, only
two fulfilled the required neurosonological features of CCSVI (Krogias et al., 2010). The
group of Doepp et al. (Berlin, Germany), having a large experience of venous
neurosonography, performed an extended study protocol in 56 MS-patients. None fulfilled
the criteria for CCSVI (Doepp et al. 2010). At the 2010 annual meeting of the AAN, Zivadinov
et al. (Buffalo, USA) reported the presence of venous construction in more than 50% of MS
patients, whilst CCSVI was also detected in about 30 % of the healthy controls (Zivadinov et
al., 2010).
An Italian group from Padua (Baracchini et al., 2011) recently performed a very interesting
study investigating 50 patients with a clinically isolated syndrome (CIS) and with additional
evidence of dissemination in space of the inflammatory lesions (possible MS). In only eight
(16%) of them were the CCSVI criteria fulfilled. In seven, additional selective phlebography
was performed, revealing hypoplasia of internal jugular vein in one case as the only venous
abnormality within the whole series. If CCSVI causes MS, one would expect the presence of
CCSVI already at the onset of the disease. The findings of this Italian study do not support a
causal relationship between CCSVI and MS.
These results are of special interest since Prof. Zamboni promotes endovascular intervention
as a groundbreaking treatment of MS. An open-label trial was published by Zamboni et al. in
the ?Journal of Vascular Surgery? in 2009. In 65 patients with MS percutaneous transluminal
angioplasty (PTA) was performed (Zamboni et al., 2009b). Most of the patients were on
disease-modifying therapies. There was a lack of a control group. The authors claimed that
this procedure has led to an improvement of the clinical outcome in relapsing-remitting MS
(RRMS) patients. Being aware about the high variability of MS disease course, the
improvement described may reflect the natural outcome, as clinical relapses mostly show
remission. The effect on the annual relapse rate was not different from that reported from
placebo treatment in placebo-controlled clinical trials. In patients with progressive forms of
the disease no improvement was observed after PTA. Zamboni self-proclaimed this
intervention as ?liberation procedure?. Unfortunately, such a name raises inappropriate
expectations among MS patients.
Recently, a third German group (Frankfurt/Giessen) performed a sonographic study
investigating 20 MS patients and 20 controls (Mayer et al., 2011). The only subject fulfilling
the CCSVI-criteria was a subject from the healthy control group. As these findings cast
serious doubt on the concept of CCSVI in MS, the authors entitle appropriately their paper
?The perfect crime? CCSVI not leaving a trace in MS?
Conclusion and recommendations
Based on these extensive, scientifically solid data obtained from investigators outside of
Ferrara, we see no rationale to support CCSVI as a key pathogenetic factor in MS.
Furthermore an ongoing large multi-center Italian epidemiological study recruiting more than
1000 MS patients and about 1000 healthy controls and patients with other
neurodegenerative diseases, promoted by the Italian Foundation of Multiple Sclerosis and
endorsed by the Italian Society of Neurology will greatly augment our scientific knowledge
about the relationship between CCSVI and MS.
There is the theoretical possibility that the venous drainage of autoimmune lymphocytes from
the brain may cause some endothelial changes during the longstanding disease course of
MS, maybe in combination with immunosuppressive therapies. Yet even if this were the
case, this is insufficient to justify invasive, costly and potentially dangerous manipulations of
the deep cervical venous system in MS patients.
Therefore, both the EFNS and the ENS Multiple Sclerosis Scientist Panel and ECTRIMS
Executive Committee emphasize the high risk and absence of a scientific basis for ?liberation
procedures? in MS patients. All societies are in full accord with the Multiple Sclerosis
International Federation statement on CCSVI
(http://www.msif.org/en/research/msif_on_ccsvi.html)
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